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miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-11-24 , DOI: 10.1016/j.omtn.2018.11.010
Yanan Lu , Shuting Song , Xiaoxue Jiang , Qiuyu Meng , Chen Wang , Xiaonan Li , Yuxin Yang , Xiaoru Xin , Qidi Zheng , Liyan Wang , Hu Pu , Xin Gui , Tianming Li , Dongdong Lu

miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex’s occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.



中文翻译:

miR675通过阻止DNA错配修复促进间充质干细胞的恶性转化

miR675在几种人类肿瘤组织中高度表达,并积极调节细胞进程。在本文中,我们证明了miR675可以促进人间充质干细胞的恶性转化。从机理上讲,我们揭示了miR675增强了多泛素结合蛋白p62的表达。有趣的是,P62与SETD2竞争结合组蛋白H3,然后显着降低SETD2与底物组蛋白H3的结合能力,从而大大触发组蛋白H3第36个赖氨酸(H3K36me3)的三个甲基化的减少。因此,H3K36me3-hMSH6-SKP2三元复合物显着降低。值得注意的是,三元复合物在染色体上的占有能力绝对降低,阻止了其对DNA损伤的修复。凭借SKP2的老化组蛋白H3.3的还原降解能力,该组蛋白与DNA错配,组蛋白H3.3的老化修复被延迟。因此,错配的DNA逃脱了修复,触发了几个细胞周期相关基因的异常表达,并导致间充质干细胞的恶性转化。这些观察结果强烈表明,了解miR675的新功能将有助于开发多种癌症类型的新型治疗方法。

更新日期:2018-11-24
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